The interaction of antibodies and antibody-antigen complexes with cells of the immune system effects a variety of responses, including antibody dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), phagocytosis, inflammatory mediator release, clearance of antigen, and antibody half-life. Antibody constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions. Depending on the amino acid sequence of the constant region of their heavy chains, antibodies or immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, and IgG4; IgA1 and IgA2. Papain digestion of antibodies produces two identical antigen binding fragments, called Fab fragments, each with a single antigen binding site, and a residual “Fc” fragment, whose name reflects its ability to crystallize readily. The Fc region is central to the effector functions of antibodies.
It is known that administration of intravenous IgG (IVIG) mediates both pro- and anti-inflammatory activities through interactions mediated by its Fc fragment. Thus, IVIG is known as a therapeutic preparation which has been approved for the treatment of patients suffering from a number of autoimmune diseases, including immune-mediated thrombocytopenia, chronic inflammatory demyelinating polyneuropathy, and Guillain-Barre syndrome, as well as other autoimmune disorders.
PCT International Application Number PCT/US2007/008396 (WO 2007/117505) discloses that the anti-inflammatory activity of IVIG is a property of the Fc fragment and its linked glycan, requiring terminal α2,6 sialic acid linkages, indicating a combined requirement for the specific polypeptide backbone and glycan structure for immunosuppression. (see also Anthony, et al., 2008, Science 320: 373-376).
Nimmerjahn and Ravetch (2007, J. Exp. Med. 204: 11-15) review and disclose technology related to the use of high doses of IVIG for treating various immune disorders. The authors present several relevant models which might explain the means through which intravenous (IVIG) suppresses pathogenic inflammatory responses. To this end, a two cell model forwarded by the authors suggests that sialylated IgG interacts with a putative IgG receptor on a regulatory cell, such as a macrophage, which in turn would up-regulate expression of inhibitory FcγR expression on an effector macrophage. However, no specific receptor is identified.
It would be desirable to identify new compounds useful in treating inflammation associated with various immune disorders. Such methodology might be more plausible subsequent to identification of the receptor(s) which interact with and promote this IVIG-related anti-inflammatory activity. To this end, the present invention addresses and meets this need by identifying the receptor type which interacts with a sialylated IgG antibody or Fc fragment associated with IVIG therapy, thus allowing for methods and assays useful in identifying new drugs to complement or supplant existing IVIG-based treatment of autoimmune disorders.